A promising and widely studied example of vertebrate synaptic plasticity is long-term potentiation (LTP), the persistent synaptic enhancement seen following a brief period of coincident pre- and postsynaptic activity. The cellular and molecular mechanisms responsible for LTP are thought to participate in physiological and pathological processes including learning, memory, developmental synapse specificity, pain, neuronal death, and dementia. For many years the locus undergoing changes during LTP (pre- and/or postsynaptic) was debated. Identification of the post-synapse as a site of modification has led to considerable advancement in the field. Evidence accrued over the past ten years indicates that delivery of AMPA-type glutamate receptors to synapses plays a critical role during LTP. However, the mechanisms controlling synaptic incorporation of AMPA receptors are not clear. In particular, the path by which AMPA receptors reach synapses during LTP, lateral diffusion and/or exocytosis, is hotly contested. Since these paths employ such mechanistically distinct processes, knowing each of their roles will shed light on the underlying molecular machinery operating during LTP. We have developed molecular, optical and electrophysiological methods in rodent brain slices to elucidate the mechanisms controlling AMPA receptor synaptic incorporation during LTP and experience-driven plasticity. In this grant period we plan to: 1. Measure optically synaptic incorporation of recombinant AMPA receptors. 2. Determine the role played by AMPA receptor exocytosis in LTP. 3. Determine the role played by AMPA receptor lateral diffusion in LTP. 4. Determine the pattern of synaptic potentiation in single neurons following experience-driven plasticity. PUBLIC HEALTH RELEVANCE: Synapses, the sites of communication between nerve cells, are modified during learning and memory. How this modification takes place, at the molecular level, will help scientists understand the biological basis of learning and memory, as well as what goes wrong during diseases such as Alzheimer's disease.